Ricinoleic acid ester solutions of adreno-cortical hormones



RICINOLEIC ACID ESTER SOLUTIONS OF 'ADRENO-CORTICAL HORMONES Alberto Ercoli, Milan, Italy, assignor to Francesco Visj mara Societa per Azioni, Como,'Italy, a corporation of Italy, and Alberto Ercoli, Milan Italy No Drawing. Filed Oct. 15, 1957, Ser. No. 690,201

6 Claims. (Cl. 167-77) This invention is concerned with improvements in or. relating to pharmaceutical compositions, more particularly with oily solutions for parenteral administration of adreno-cortical hormones.

The preparation of oily solutions of cortical hormones,- such as cortisone and hydrocortisone, or of their corresponding A dehydro derivatives, 9-halogen and/or G-methyl-derivatives, in sufficiently high concentrations required for many therapeutic purposes has been a problem.

It is well known, in fact, that these hormones, as well as their esters which may be used in therapy, are very sparingly soluble in the oily solvents which :are com-. monly employed as vehicles for parenteral use e.g. olive oil, cottonseed oil, sesame oil, arachis oil or ethyl oleate. For this reason these hormones are usually administered parenterally in aqueous suspension or orally. Both these forms of administration have shown, however, anumber ofsignificantdisadvantages. r 1 ui'Aqueous suspensions arennot always, well tolerated. The crystalline deposit is usually absorbed from the, site of injection at too slow a rate. Thepoo'r absorption may cause phenomena of local intolerance;. iA-queous suspensionsimaymalso give rise, especially in prolonged treatments, .toliriitations 1 at the site of injection, which sometimes vform abscesses.

, .Oral administration.doestnot always assure regularity as well a's constancy of action; and does not guarantee solutions with'a high hormonal concentration which'are of considerable :importance. in the'rtreatment of" certain diseases whereLhigh doses of the hormone: are :required. :,.I, Further objects will become apparent as the description proceeds. r l It has now been found that verysatisfactory parenterally acceptable solutions of adreno-corticalhormones may .be prepared by :u in esters of'ricinoleic acidwith certain fmono and polyhydric alcohols as solvents;:such:solutioi1s ere adap

p f course contain'zother .adjuvantswhich arenot esters bu'tt'rwliich are parenterally J acceptable jand' phairf compatible' th'e "th suchas'tantioiiiflanf 2,983,649 Patented May 9, 1961 prising one or more, adreno-cortical hormones in' solution in a liquid vehicle consisting of one or more parenterallyacceptable esters of ricinoleic acid with a monohydric or polyhydric alcohol containing two or three carbon atoms per molecule. The composition may contain, if

desired, other parenterally-acceptable compatible adjuvants which are not esters.

By the, term adreno-cortical hormone is to be understood steroid compounds having adreno-cortical activity.-

or ethyl alcohol are preferred because of their high sol- 'ubilizing power and of their good local tolerance.

. The oily solutions according to the invention are welltolerated, well-absorbed at the site of injection andjaccompanied byrelatively few side-efiects, even incases where high doses are administered. 'llhey possess a high therapeutic value which makes them active atsmall doses not otherwise effective, as, for instance, in the liver glycogen deposition test where, at equal doses, prednisone inan oily solution has been shown to have an activity five time'slliiglier thanthat of the oral form (thatisin order to obtain thesame increase in liver glycogeman oral dosefive times higher than that administered par; enterally in oily formmustjbe given). I Although'the adreno-cor'ticalhormoneused'in the oily compositionaccording to thejin'vention may be"anyf de sired such compound it is" preferred to use a compoiifid of thejgeneral formulaz' 1 where p i X is ketonic oxygen or a h yd rolr yl,group, .Y is a hydrogen or a halogenatoin, .1 Z isa hydrogen atom or methyl group, and R is hydrogen or .an acyl; group preferably cont g desired ohetmay usedn irrt uresgof adi'eno cortical vehicles in various pr These Par a not more than .11 carbonuatoms per l molecule or use d eitherindividually. er in s atoms per molecule, such as olive oil, sesame oil, ethyl oleate, or benzyl benzoate.

The mixtures, for example with ethyl oleate, have a solubilising power inferior to that of pure ricinoleates;

-Substances of this nature include, for. example. sex

hormones and products related to steroid hormones.

Moreover, one may add to the composition desired pharmaceutically acceptable adjuvants such'as antioxima ma cal hormones;

on the other hand, they have the advantage of a lower dants and conserving or antiseptic agents (such as monov'iscosity, so that injection becomes easier. or polyhydric phenols and ethers thereof) to prolong Tables 1 and 2 show the solubilities of cortisone, the stability of the components of the composition. prednisone and prednisolone and of some of their esters In order that the invention may bewell understood, in the-ricinoleic acid esters, as compared with their, re.- the following examples are given by way of illustration spective solubilities inoliveoilior sesame oil. only.

" TABLEI Cortisone Cortisone Cortisone cortisone trlmethyl- Cortisone cyelophenylaeetate, acetate, oenanthate pentylproplonate, mg;/ce. mgJcc. mg./cc., propio/nate, rng'Jcc.

.. mg.ec.-

Olive 011.: I Q 0.1 0.1 s r 3 3 Glyeeryl rlclnoleate" 5 3 60 40 3O gf v g qa 3 60 40 26 p 4 m. i fiia r em ea 2 5(0) 40(a) G1 1"iln1t t 1 t a are$2-323:--13211 4 2.5 50 2.

a) rieinoleatje=l: I, i I (b).=Glycery1 rlcinoleatezethyl rlctnoleate=1:2.

' TABLE 2 Prednlsone Prednlsone Prednisone Prednisone Predni- Prednl- Predntsone, acetate, trimethyln n n h cyclopentylsolone, solone mgJec. mgJcc. acetate, lug/cc. propionate, mgJec. oenanthate, mgJec. mg.lcc. mgJcc.

Sesame oll. 2 2 1v 3 2 1 6 Glycenylrlcinoleate 12 10 8 I 12 10 25 60 Ethylricinoleate 1O 7 20 Glyceryl ricinoleate+Ethyl rlctno1eate. 8 9 4' 10 10 32 Glyceryl rlclnoleaterl-Ethyl oleate 1 :1.... ,7 3.8 I I 9 8 16 v The adreno-cortical hormones can .be dissolved in the I I I Example 1 v ngniqlew-acld eS.terS aione or aidinixtureiwlth 40 .Cortisone .trimethylacetate (5 g.) was ground to a such esters and n various proportions as stated above. fine powderiand suspended in a two litre mixture of Moreover different esters of the sameho'rmone or various cryl and ethyl ricin01eates 5 mgflitre of propyl of ldlfierent P i. dlstsolved latexand 'nordihydroguaiaretic acid .(in equal parts). were s s i t m whic or m amlx-turetof different added; The mixture was. heated on a water-bath with y a suitableimixture oi as esters occasional shaking of the suspension so as'toobtain a at i same'hormone ig??? 95 2 Olly 1- clearjand homogeneous solution. The .resultantsolution be obtame W1 g ormonal Was'then; transferred into neutral glass' 2:cc.la mpoules, centrafloneach ampdulelthuscontainihgS mg. of cortisonetnm' ethyl- The solutions thus obtamed show a substantlally acetata The ampoules sealed under nitfogen-fiwere normal viscosity after the'addition of correctives and sterilised at artemperamk bf 1209 C for they pracflcally'stabrle-gand i advant.ageous and Anurhber of the ampoules wereused for biological effectlve than the igneous 'suspenslons' PPCVIWSEY experiments. .The remainder were maintainedfor some 7 p08?! and also than-(gal i y They ensure m fact weeks inthe ice-chest and then for some months at room i a hlgher constancy of actlon W more marked eflects temperature. The .ampoules thus treated remained per.- g; -35 8 i h fectly clear and homogeneous, even after many months erapy W1 Sue -P? as gwlm had elapsed from the date ofttheir preparation; The'addifavourable results- T Olly iomposltlons of colftlcal tion of small crystals of cortisone trimethylacetatetfailed hormones and, partlcularly, those of the antireactronal .to'causeeitheropalescenceOrth formation df ale ryst hormones, have ben found to possess a generally 'SIIPQI'IOI I line precipitate V 1 I tPeraPeutw value i ha i m by aqueous lsuspeil The comparison of the biological activity of the oily slolns or h 55 93? t d 1 solution of cortisone trimethylacetate' was {carried out 1 l P i 9mm: articuar withsan'. aqueous suspension iof cortisoneacetateat1 the st w ea es diseases e e syndromes etc-t ms rai g/cc.) using the tester the sur-' l f ab l g q h been i to glve' optlmal' vival of adrenalectomised rats treated with one single I 'chmcfal remlsslonswlthidosgs lower im normally injection of the steroid The test was carried out-on F W 15 mgmsof male rats, 30 daysx'old and weighing 60 each. Bi-' PF.- 9 ll haveglven results mP lateral \adrenalectomy was: carried out under ether narfi g gg z g figig g zfi igg g fifma g ge fi I I .cosis, according to the Grollrnams technique. 3-4 hours i 7: y Wei fibin ,fiie; afternthe; adrenalectomy, the 'animalsi were subdivided mto .twolgroups joff ten animalsxeach 'jAllthe animals of; one group' were: treated with one singlevinjectionof g of cortisone acetate in aqueous: suspensio sin e i j ti f.' 2*5 ,m of

the animals of the other group were treatedjwithjone Qortisone ftnimethylacetatej r homogeneous solution.

as controls. The results obtained are shown in the following table.

TABLE 3 Number of living animals Treated with V Treated with Days alter intervention 2.5 mg. of 2.5 mg. of l y Untreated cortisone cortisone acetate in trimethylaqueous acetate in suspension oily solution Example 2 Cortisone oenanthate (500 g., M.P. l38-140 C.), cortisone cyclopentyl-propionate (300 g., M.P. 154-156 C.) and cortisone phenyl-propionate (200 g., MP. 173-- 175 C.) were suspended in a 20 litre mixture of glyceryl triricinoleate and ethyl oleate (1:1), containing nordihydroguaiaretic acid in the proportion of mg/litre. The iiiixturewas stirred mechanically, the internal tempera ture being kept at 100" C. so as to obtain a clear and This solution was then introduced'into 2 cc. ampou1es,so that each one contained eiractly 100 mg. of themixture of the cortisone esters ing./cc.). The. ampoules, sealed under-nitrogen, were sterilised at a temperature of 120 C. for about SOfm'inut es. When the exceptionof some of these ampoulesj 'whichwerej used for biological experiments, the remainder were maintained for a few weeks, at about 0 C. in an'ice-chest, then for some months at room temperature. None of the ampoules thus treated showed ftjdrbidity orf precipitate even a few months after thedat'oftheir preparation.

. 1 Exampled 1 V A-mix'ture of cortisone trimethylacetateKIOO g., M. P. 260-362 'C.), dehydrocorticosterone trimethylacetate (100 g., M.P l86l87 C.) and desoxycorticosterone' triinethylacetate (100 g., MP. 200-202 C.)-was dis-. solved at 'a temperature of' about 80 C.,' in a 40 litre solutionfof ethyl ricinoleate diluted with l0%*of ethyl oleate and containing, in the proportion of 8 mg./litre,

' heated on a water-bathjthefsuspension being occasionally shalgen and the ternperature slowlyraised untildisso lution was" complete. The clear and' homogeneouls solu:

tionfthusbbtained'was iiitroduced' into-2 cc. ampoules so that eachampoule contained exactly 24 mg. of prednis'oire oenanthate. The ampoules were closed in 'a nitrogen f atmosphere, sterilised, and then maintained for some weeks in the ice-chest. The solution'inside the ampoules rtremained quite clear and homogeneous and was practical ly'uncong'ealable. J In the lsame way, prednisonejcyclopentyl propionate (753,, MP. 188- -l,C.) were dissolved in 7.5"litres of a mixedsolution of glyceryl and ethyl ricinole'atesfto which had been added, in the proportion of 5 mg./litr e, nordihydroguaiaretic acid. The solution thus obtained was introduced into 10 cc. containers. (Each container thus contained 100 mg. of prednisone cyclopentylprop ionate.) A few months after the date ofpreparation the solution inside the containers was-still perfectly homogeneous. There was no formation of any precipitate, even after the addition of seed crystals of pre'dnisfone cyclopentylpropionate. Y t l In the same manner as aboveprednisone was dissolved in a mixture of glyceryland ethyl ricinoleates"( lil)l The biological activity of the prednisonefiadministeretl parenterally, in oily solution, was compared. with that or prednisone administered orally. The comparison-was carried out on albino rats and the; action on thymus, adrenals'and body weight was obtained. 1 t i The liposoluble prednisone was administered'in doses 'of 50-100-200-400 and the orally administered pi-ed nisonein doses of 100-'200-400-600-1000 treat} ment was continued' for five consecutive days; on-the 6th day the animals were sacrificed; the adrenals; and thymus were removed and weighed immediately; 'fl'he results areishown in the table below.

. TABLE 4 t j Animals, Body weight 7 Adrenals Thymus Treatment No. change, weight, weight,

Percent Percent Percent l Controls 31 107. 7':l:1. 26 13. 15:0. 36 89. 4:1:4. 79

400 x 12 85. 2:1:1. 29 7. 75:0. 21 l6.-1:l:0. 26

1100 X 5- (12 103. 8:1:3. 10 11. Bill. 60 36. :5. 19

.50 X o 6 102. 6&2. 92 13. 15:0. 54 57. 7:1:6. 08 Prednisone per os: i l

. 1,000 X 5 l 6 L 106. 1:}:2. 23 11. 0:1:0. 81 23. 1:1:1'. 95 600 x 5- 6 105. (id-,2. 50 '13. 0:1:0. 44 41. 0:1:2. 59 400x 5- 12 108. 4:1:2. 69 12. 4:]:0. 56 43. 2:1:4. 12 200 X 5 19 109. 3:1:1. 44 12. 8:1:0. 88 l 61. 5:1:3. 74 X 5 6 104. 8:1:2. 23 13. 6:1:0. 89 50.0:h6. 16

These results show that, with regardto th e {activity on'thymus adrenals and body weight, me prednisone preparation in oily solution administered in'tramuscularly is much more active ,than the orally administered prednisone. in. L9:

HYdfQOl'tlSQlTQ acetate (15 7MP. 1219:2207) as dissolved by heatingin 1.5 litres of proplyenyl ricinoleate; prepared by esterific ation of rieinoleic acidwith propylene glycol. The solution (containingj 20 mg. of hydrdcorti sone acetate per cc.) -was introduced-into 2 cc. ampoules which were then sealed under vacuum "and sterilized in an autoclave.

The ampoule solution wasbiologically tested-after diluting 1:10 with sesame oil or itsefiects on the survival of adrehalectomised rats and. its was found to be very effective. T

m l dl N .11 1 Prednis'olone (100 g., M.P.L.240-242. C;) was' dis solved by heating tiny-a mixtureiof ethylricinoleateand ethyl oleate (1:1) to givea concentration oflS mgJcc; Multidose containers '(10 cc.) were filled with this solution in .the usual manner, sealed and sterilisedq Eatampiq 7 Q 'for"use inparenteral administration wereprepatedwith 1 other steroids using 'glyc'eryl, propylenyl and ethylricincr. 5

leates-singly and in admixture as'the liquid vehicle.

Among the steroids made :up into suchpreparations' were 9a-fluoro derivatives of prednisone and prednisolone and their corresponding Afi-dehydro ore-methyl derivatives. i.e.: 9a-fluoro A pregnadiene-11p:l7a:21ttio1 nordihydroguaiareticacid and propyl parts, in theproportion' 0158 mg./ litre. -:.-The';c1ear1solution was then introduced into J 9e-f QrQ- 6 t o t2 li n t V 1 1, n E a p Brednisone trimethylacetateTS g.) was groundto. a fine-powderand suspended in a two litre mixture of gly ceryl and ethyl ricinoleates, 5 mg./1itre of propyl gallate and nqrdihydro'guaiaretic acid n equal p s) w then added. The mixture was heated on a water-bath, the euspension being occasionally shaken and the temperature slow1y raised: until a clear and homogeneous solution was obtained, This solution was then transferred into neutral glass 2 cc. arnpoules, each ampoule :thus haying 8 mg. of prednisone trimethylacetate. The arm poules, sealed under nitrogen and sterilised, were maintained for some weeks in an ice-chest and then for some months atroom temperature. The ampoules thus treated remained perfectly clear and homogeneous, even after many months had elapsed from the date of their prepare: tionv 1 Eyenthe addition of small crystals of prednisone trii'nethyl etatecaused neither opalescence nor crytalline Prec i a ion, r The biological t i y of pred isone ime ylacetate in the above vehicle was compared to that of the prednisone orally administered. On the turpentine granuloma test prednisone' trimethylacetate in oily solution showed an anti-inflammatory power clearly superior to that'of the prednispne, administerd by .oral route.

Example 9 Prednisone n-irnethylacetate (35 g., M.P. 274-278" C.), prednisone oenanthate (8.0 g. M.P. 176,-178T' C.) and prednisone cyclopentyl-propionate (75 g., MrP. 188 -190" C.) were suspended in a '10 litre mixture of glyceryl tri-. ricinoleate and ethyl oleate (1:1), containing nordihydroguaiaretic acid in the proportion of 10 rug/litre. The mixture was stirred mechanically, the internal temperature being kept at 100C. so as to obtain a clear and homogeneous" solution. This solution'w as then introdncedlin't'o 2"cc; ampoules, so thatea'ch contained exactly 38' g. of the mixture of the prednisone esters (19 [The ampoules, sealed under "nitrogen, were tr g/cc); J Sterilisedat a temperature of120 'C. 'for'about 30 rnifnjutes. After a few weeks at about 0 C. they were mai'ntained for some months. at roomtemperature. None of the mpules thus-treated showed any turbidity. or 1, preci ate van a few months after 'the dateoftheirprepan jilytsiolutio'n of the prednis'on'e esters were plog lly tested-after iatdilution 1 10 with sesame oil-.4 iftjr .eflects on the 'snryiv'al of the adrenalectomised rats and it' was found to be very effective.

' f twEa cample 10.1 t a wer "of. inred is ne t' imeth ase a e 5 o; predisolone' trimethylacetate (55" g.) and t g t 'fl uoro prednisolone trimethylacetate (30 g.) was dissolved, at

a temperature of about'SU C.,'in a 5 litre solution of ethyl ricinol'eate containing 10% of ethyl oleate and gallate, in vequal 500 containers of'*'-10f cc.:each; so'tthat'each contained-200 mg: of the trimethy-l-acetate mixture.

1 In the same manner; prednis one oenanthate (20 g.) and -prednisolone-oenanthate ,(8Q g) were dissolved in molecule.

1. An oily composition adapted for parenteralad-e ministration comprising at least one adreno-cortical hormone selected from the group consisting of adrenocortical hormones of the general formula:

onion where X is selected from the group consisting of an oxygen atom and a hydroxyl group; R is selected from the-group consisting of a hydrogen atom acyl group derived from a monocarboxylic acid containing not more than 11, carbon atoms per molecule, the corresponding A and-A i compounds in solution'in a liquid vehicle consisting of at least one ester of ricinoleic acid with an alcohol selected from the group consisting of lmonoand polyhydric alcohols containing at least 2 and 'not more than 3 carbon atoms per molecule v t a 2. An oily composition as defined in claim '1 also con; taining an anti-oxidant. r I a 3, An oily composition as defined in claim 1, said adreno-cortical hormone is present in an amountot 0.10.4% by weight ofsaidliquid vehicle.

4. An oily composition as defined in claim 1 in which saidjesifirllis an ester of ricinoleictacid with an'alcohol sele t d" fr m e gro p icnn i tin of e h a e hcli P opy n ly and y ol i 5. 'An oily composition as defined inclaim l alsoeon;

taining a further ester component consisting of an of an alcohol with a carboxylic acid other thanricinp leic acid, said ester containing at least six carbonatoms per 6. An oily composition as defined in cIaimS said ester is, selected from the group consisting of olive o esame o eth o e te and enz enz n f'lR s e ae Cited in ha le t hi r test 1 UNITED STATES PATENTS 2,661,315 Jurist et al. Dec. 1, 1953 ,76 ,112 k a er 1- s 23,

Richter 3 5 6; 7 .7 i t O THER nEne EN es ILS. Dispens/at ry, thue tri t u 1 5 s I 1 Mi l t ziz .Gazzetta Medica Italiana, Minerva Medici! Ea -115,; 11, November 9 PPes r' P' P I e note. .t ,7 I? i 

1. AN OILY COMPOSITION ADAPTED FOR PARENTERAL ADMINISTRATION COMPRISING AT LEAST ONE ADRENO-CORTICAL HORMONE SELECTED FROM THE GROUP CONSISTING OF ADRENOCORTICAL HORMONES OF THE GENERAL FORMULA: 